Systemic corticosteriod rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients.

There is evidence that downregulation and desensitization of airway beta 2-adrenoceptors (beta 2-AR) develops after continuous exposure to long-acting beta 2-agonists such as formoterol and salmeterol. To investigate the facilitatory effects of acute administration of systemic corticosteroid on bronchodilator subsensitivity, as might occur in the setting of acute asthma, 12 subjects with moderately severe asthma, with a mean FEV1 of 66% predicted, of whom were all receiving inhaled corticosteriod, were randomized to receive either inhaled placebo (PL) or inhaled formoterol (FM) 24 micrograms twice daily for 4 wk in a double-blind crossover study. Subjects were also genotyped in terms of beta 2-Ar polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 108 micrograms) was produced 1 h after administration of placebo tablets and after injection at 3 wk, and 1 h after administration of oral prednisolone, 50 mg, and intravenous hydrocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for delta FEV1 (as AUC, L.h): 2.51 versus 4.22 (95% CI: 0.54 to 2.89; p = 0.01) and delta FEF25-75 (as AUC, L x 10(3)): 11.30 versus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly reversed by steroid (S) for FEV1 (FM versus FM+5): 2.51 versus 3.57 (95% CI: 0.11 to 2.27; p = 0.03) and for FEF25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte beta 2-AR density (log Bmax; fmol/10(6) cells) showed significant upregulation 3 h after steroid (FM+5 versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivity with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.001), and this was reversed by steroid (FM+5 versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic corticosteroid appears to be generally independent of beta 2-AR polymorphism at loci 16 and 27. In conclusion, we have demonstrated that bronchodilator subsensitivity occurs after regular inhaled FM in asthmatic patients, and is rapidly reversed by systemic corticosteroid. Thus, in acute asthma, systemic corticosteroid should be administered a soon as possible, in order to restore normal airway beta 2-AR sensitivity, particularly in patients who are receiving regular long-acting beta 2-agonists.

Bambuterol in the treatment of asthma. A placebo-controlled comparison of once-daily morning vs evening administration.

Once-daily morning (7 AM) vs evening (10 PM) administration of the terbutaline prodrug bambuterol (20-mg tablet dose) was investigated in a double-blind, cross-over, randomized, and placebo-controlled study involving 29 diurnally active patients with asthma. Terbutaline plasma concentration, spirometry, and drug tolerance were assessed during 39-h inpatient studies. A 7-day washout period separated each treatment. Mean 24-h plasma concentration was comparable for morning and evening bambuterol (13.2 vs 14.0 nmol/L). The Cmax for evening vs morning dosing was 17.2 vs 15.5 nmol/L (p < 0.02). The 24-h mean FEV1 was greater (p < 0.001) for bambuterol (morning: 3.2 L; evening: 3.4 L) vs placebo (2.9 L) as it was for FVC, FEF25-75%, and peak expiratory flow rate (PEFR), with the maximum effect at 4 AM independent of medication time. Evening dosing, however, resulted in greatest 7 AM (awakening) FEV1, FEV25-75, and PEFR (p < 0.03). With reference to corresponding-in-time placebo values, improvement in FEV1 at the end of the 24-h dosing intervals amounted to 0.34 L (13.5%) (p < 0.0004) and 0.35 L (15.9%) (p < 0.0012) with evening and morning bambuterol dosing, respectively. Side effects were greater for bambuterol than placebo, but not significantly so. Once-daily bambuterol therapy proved to be an effective treatment for asthma, whether administered in the evening or morning. Evening dosing seems best for nocturnal asthma since airway patency overnight and on awakening at 7 AM is most improved.

Comparison between a new once-daily, bronchodilating drug, bambuterol, and terbutaline sustained-release, twice daily.

Bambuterol is a prodrug, from which terbutaline is slowly generated. The objectives of the study were to evaluate whether bambuterol, given once daily, can control symptoms in asthmatic patients and to compare the bronchodilating effect and the side effects with those of terbutaline sustained-release (SR) tablets given twice daily. Twenty-five out-patients with bronchial asthma were treated during two consecutive 14-day periods with either 30 mg bambuterol tablets once every evening or 2 x 5 mg terbutaline SR tablets morning and evening. The study had a double-blind, cross-over and randomized design. The mean evening peak expiratory flow rate (PEFR) (i.e. 24 h after intake of bambuterol and 12 h after intake of terbutaline SR) was significantly (p less than 0.001) higher during bambuterol than during terbutaline treatment (432 vs 415 l/min). The need for beta-adrenoceptor agonist aerosol in the daytime was significantly (p less than 0.05) lower during treatment with bambuterol once daily (0.70 puffs) than with terbutaline SR b.i.d. (1.04 puffs). The type and intensity of the side effects were the same during both treatments.

Bambuterol: clinical effects of different doses of a long-acting bronchodilator prodrug.

Sixty-eight asthmatics participated in a dose-finding study on bambuterol, a terbutaline prodrug, administered once every evening. Bambuterol administrations of 0.185, 0.270 and 0.400 mg/kg gave effective and long-lasting bronchodilation, for at least 24 h, with the two higher doses probably close to the maximal effect of the drug. Bambuterol 0.400 mg/kg was associated with more adverse effects than bambuterol 0.185 mg/kg. The side effects were those expected in oral beta 2-agonist treatment and mainly experienced by patients who had not been on oral beta 2-agonists before. The most favourable of the investigated doses was found to be 0.270 mg/kg. It can not be excluded, however, that a somewhat lower dose may still be as beneficial. This will be investigated in forthcoming studies.

Bambuterol: dose response study of a new terbutaline prodrug in asthma.

The bronchodilator activity and side-effects of treatment for 4 days with either 0.085, 0.170 or 0.34 mg/kg bambuterol b.i.d. (a prodrug of terbutaline) or 0.071 mg/kg terbutaline t.i.d. have been evaluated over 12 h, in a double-blind, randomized crossover trial in 19 asthmatic out-patients. Plasma terbutaline concentrations after bambuterol administration were smoother, with a ratio between the maximum and minimum values of about 1.4 compared to 2.6 for terbutaline. The plasma terbutaline level rose with dose, but by less than the increase in dose. The bronchodilator effect was related to the plasma terbutaline concentration in each treatment group, so bambuterol produced more prolonged bronchodilatation than treatment with terbutaline. Tremor and cardiac side-effects were most pronounced after administration of bambuterol 0.34 mg/kg. No severe side-effects were seen. Bambuterol produced stable plasma levels of terbutaline, indicating that as a prodrug of terbutaline it might possibly be administered once daily with good antiasthmatic effect.

Long-term oral therapy of asthma with terbutaline and theophylline, alone and combined.

Bronchodilation and side effects of 28 days treatment with either a full therapeutic dose of theophylline slow-release preparation 500 mg twice daily (400-600 mg), a slow-release terbutaline preparation 10 mg twice daily or combinations of the 2 drugs in full or half doses were evaluated in 31 asthmatic outpatients in a double-blind, randomized crossover design. The combination of half doses of the 2 drugs produced slightly better bronchodilation than high-dose, single drug regimen and similar bronchodilation as a high-dose combination. Side effects during half dose combination were less than when theophylline alone or high dose combination treatment were administered. High-dose combination treatment produced slightly more ventricular ectopic beats and supra ventricular ectopic beats, and 3 patients developed cardiac arrhythmias. A combination of half the normally used doses of oral slow-release formulations of terbutaline and theophylline seems superior to a high-dose combination.

Bambuterol: effects of a new anti-asthmatic drug.

Twenty-seven asthmatic outpatients were randomly treated with bambuterol 30 mg administered once daily before going to bed and sustained release terbutaline 10 mg twice daily in a 14 day, double blind cross over study. On all the parameters of bronchodilator effects, namely peak expiratory flow rate (PEF), use of extra beta-agonist puffs, asthma symptom score, and patient preference for one of the treatments, no statistically or clinically significant difference between the two treatments was found. No significant difference between treatments was observed in the number or severity of side-effects. Bambuterol administered once daily appears to be an effective anti-asthmatic treatment.